Severe sepsis is a major cause of mortality and morbidity in the US (Angus DC et al., 2001) with some 751,000 cases annually, costing on average over $22,000/case, and resulting in 215,000 deaths (28.6% mortality rate). The incidence of sepsis cases has been projected to increase by 1.5% per annum. Xigris, the first FDA-approved drug therapy for sepsis has been in use since .2001. However, Xigris is limited to severe sepsis patients only and shows only a 6% reduction in mortality, still leaving an enormous unmet medical need. Lactoferrin has been shown to provide protection in several models of sepsis. However, much of the work so far has been carried out with bovine lactoferrin (e.g., Lee et al., 1998; endotoxemia in neonatal piglets, mortality reduced from 83% to 26%). The use of bovine lactoferrin in humans may be limited by the lack of its pharmaceutical-grade quality. The use of native human LF is limited by its availability. Agennix has demonstrated that recombinant human lactoferrin (rhLF) given orally is efficacious in murine models of LPS-induced endotoxemia. RhLF has also been shown to be effective in attenuating the effects of bacterial infection (Edde et al., 2001), in E. coli-infected neonatal rats, the number of dead/dying animals decreased from 46% to zero (P<0.0001)). A clear unmet medical need in sepsis and the opportunity for an effective intervention offered by the observed pre-clinical efficacy of oral rhLF merits further development to make oral rhLF a subject of sound clinical investigations in sepsis indication. To this end, using both gram negative and gram positive (E. coli IPS, Staphylococcus aureus enterotoxin B toxin) challenge models, this projects aims to establish therapeutic effectiveness of rhLF by demonstrating statistical significance of the effect of oral rhLF (Specific Aim 1). Further, we plan to establish therapeutic effectiveness of oral rhLF in murine bacterial infection models (E. coli, Staphylococcus aureus), using both the systemic and gut-associated bacteremia, with and without the use of antibiotics (Specific Aim 2). The overall aim of this proposed project is to assemble experimental evidence compelling enough to allow clinical examination of the possible efficacy of rhLF in human sepsis. NIH funding for this project would directly support the development of potentially important drug therapy to treat human sepsis. [unreadable] [unreadable]